Prenatal Diagnosis of HSPG2-Related Dyssegmental Dysplasia: The First Report From Turkey.

Abstract

Silverman-Handmaker type dyssegmental dysplasia (DDSH) is a rare and lethal skeletal dysplasia caused by biallelic null variations in the HSPG2 gene, which encodes the extracellular matrix proteoglycan perlecan. Here, we report a prenatal case of DDSH identified at 18 weeks of gestation, referred due to ultrasonographic findings of limb shortening, retrognathia, and irregularities in the lumbar vertebrae. Targeted skeletal dysplasia panel testing via next-generation sequencing (NGS) revealed a novel homozygous splice site variant, c.1355 + 1 G>T, located at the canonical donor site of intron 11 in HSPG2. The fetus died shortly after birth, consistent with the expected DDSH phenotype. Our case expands the mutational spectrum of HSPG2-related skeletal dysplasias and underscores the diagnostic and prognostic challenges of novel splicing variants in prenatal genetic counseling. It also emphasizes the value of combining prenatal imaging with molecular diagnostics to improve diagnostic accuracy and support informed reproductive decision-making.